Exploring Stereochemical and Conformational Requirements at Cannabinoid Receptors for Synthetic Cannabinoids Related to SDB-006, 5F-SDB-006, CUMYL-PICA, and 5F-CUMYL-PICA

Abstract

Synthetic cannabinoid receptor agonists (SCRAs) represent the most rapidly expanding class of new psychoactive substances (NPSs). Despite the prevalence and potency of recent chiral indole-3-carboxamide SCRAs, few pharmacological data are available regarding the enantiomeric bias of these NPSs toward human CB1 and CB2 receptors. A series of homochiral indole-3-carboxamides derived from (<i>S</i>)- and (<i>R</i>)-<i>α-</i>methylbenzylamine and featuring variation of the 1-alkyl substituent were prepared, pharmacologically evaluated, and compared to related achiral congeners derived from cumyl- and benzylamine. Competitive binding assays demonstrated that all analogues derived from either enantiomer of <i>α-</i>methylbenzylamine (<b>14</b>-<b>17</b>) showed affinities for CB1 (<i>K</i>_i = 47.9-813 nM) and CB2 (<i>K</i>_i = 47.9-347 nM) that were intermediate to that of the corresponding benzylic (<b>10</b>-<b>13</b>, CB1 <i>K</i>_i = 550 nM to >10 μM; CB2 <i>K</i>_i = 61.7 nM to >10 μM) and cumyl derivatives (<b>6</b>-<b>9</b>, CB1 <i>K</i>_i = 12.6-21.4 nM; CB2 <i>K</i>_i = 2.95-24.5 nM). In a fluorometric membrane potential assay, all <i>α-</i>methylbenzyl analogues (excluding <b>17</b>) were potent, efficacious agonists of CB1 (EC₅₀ = 32-464 nM; <i>E</i>_max = 89-104%) and low efficacy agonists of CB2 (EC₅₀ = 54-500 nM; <i>E</i>_max = 52-77%), with comparable or greater potency than the benzyl analogues and much lower potency than the cumyl derivatives, consistent with binding trends. The relatively greater affinity and potency of (<i>S</i>)-<b>14</b>-<b>17</b> compared to (<i>R</i>)-<b>14</b>-<b>17</b> analogues at CB1 highlighted an enantiomeric bias for this series of SCRAs. Molecular dynamics simulations provided a conformational basis for the observed differences in agonist potency at CB1 pending benzylic substitution.